1. Field of the Invention
The present invention is directed to N-(2-chloro-5-methylthiophenyl)-Nxe2x80x2-(3-methylsulfinylphenyl)-Nxe2x80x2-methylguanidine, N-(2-chloro-5-methylsulfinylphenyl)-1-(7-trifluoromethyl-1,2,3,4-tetrahydroquinolinyl)carboximidamide, and N-(3-methylsulfinylphenyl)-N-methyl-Nxe2x80x2-(2-chloro-5-methoxyphenyl)guanidine and pharmaceutically acceptable salts thereof, and pharmaceutical compositions and therapeutic methods of treatment that comprise such compounds (xe2x80x9ccompounds of the inventionxe2x80x9d). The compounds of the invention are particularly useful for the treatment or prophylaxis of neurological injury and neurodegenerative disorders.
2. Background
A number of substituted guanidines have been reported. See, e.g., U.S. Pat. Nos. 1,411,731, 1,422,506, 1,597,233, 1,642,180, 1,672,431, 1,730,388, 1,756,315, 1,795,739, 1,850,682, 2,145,214, 2,254,009, 2,633,474, 3,117,994, 3,140,231, 3,159,676, 3,228,975, 3,248,426, 3,252,816, 3,283,003, 3,270,054, 3,301,755, 3,320,229, 3,301,775, 3,409,669, 3,479,437, 3,547951, 3,639,477, 3,681,457, 3,769,427, 3,784,643, 3,803,324, 3,908,013, 3,949,089, 3,975,533, 3,976,787, 4,060,640, 4,014,934, 4,161,541, 4,709,094, 4,906,779, 5,093,525, and 5,190,976; PCT applications WO 90/12575, WO 91/12797, WO 91/18868, WO 92/14697, WO 94/14461, WO 94/27591, WO 95/14467, WO 95/20950, H. W. Geluk, et al., J. Med. Chem., 12:712 (1969), and N. L. Reddy et al., J. Med. Chem., 37:260-267 (1994). WO 94/27591 discloses inter alia N-(2-chloro-5-methylthiophenyl)-Nxe2x80x2-(3-methylthiophenyl)-Nxe2x80x2-methylguanidine.
Nerve cell death (degeneration) can cause potentially devastating and irreversible effects for an individual and may occur e.g. as a result of stroke, heart attack or other brain or spinal chord ischemia or trauma. Additionally, nerve cell death (degeneration) occurs with neurodegenerative disorders such as Alzheimer""s disease, Parkinson""s disease, Huntington""s disease, Amyotrophic Lateral Sclerosis, Down""s Syndrome and Korsakoff""s disease.
Therapies have been investigated to treat nerve cell degeneration and related disorders, e.g., by limiting the extent of nerve cell death that may otherwise occur to an individual.
The compound MK-801 has exhibited good results in a variety of in vivo models of stroke. See B. Meldrum, Cerbrovascular Brain Metab. Rev., 2:27-57 (1990); D. Choi, Cerbrovascular Brain Metab. Rev., 2:105-147 (1990). See also Merck Index, monograph 3392, 11th ed., 1989. For example, MK-801 exhibits good activity in mouse audiogenic tests, a recognized model for evaluation of neuroprotective drugs. See, e.g., M. Tricklebank et al., European Journal of Pharmacology, 167:127-135 (1989); T. Seyfried, Federation Proceedings, 38(10):2399-2404 (1979).
However, MK-801 also has shown toxicity and further clinical development of the compound is currently uncertain. See J. W. Olney et al., Science, 244:1360-1362 (1989); W. Koek et al., J. Phamacol. Exp. Ther., 252:349-357 (1990); F. R. Sharp et al., Society for Neuroscience Abstr., abstr. no. 482.3 (1992).
It thus would be highly desirable to have new neuroprotection therapies.
In a first preferred aspect, the present invention provides N-(2-chloro-5-methylthiophenyl)-Nxe2x80x2-(3-methylsulfinylphenyl)-Nxe2x80x2-methylguanidine, and pharmaceutically acceptable salts thereof, i.e. the compound of the following structure (I): 
and pharmaceutically acceptable salts thereof. References herein to xe2x80x9ccompound (I)xe2x80x9d refer to the compound of the above structure as well as pharmaceutically acceptable salts of N-(2-chloro-5-methylthiophenyl)-Nxe2x80x2-(3-methylsulfinylphenyl)-Nxe2x80x2-methylguanidine.
The invention also includes optically enriched mixtures of compound (I). As can be seen from the above structure, the sulfur of the 3-methylsulfinyl group is chiral. An optically enriched mixture of compound (I) contains substantially more (e.g. about 60 mole %, 70 mole %, 80 mole % or 90 mole % or more) of one enantiomer than the other enantiomer. For use in the therapeutic methods of the invention, preferably a substantially pure optically active mixture is employed, e.g. a mixture containing at least about 92 mole %, or 95 mole % or even 97 mole %, 98 mole % or 99 mole % or more of one enantiomer of compound (I).
More specifically, the invention includes following optically active (xe2x88x92)-N-(2-chloro-5-methylthiophenyl)-Nxe2x80x2-(3-methylsulfinylphenyl)-Nxe2x80x2-methylguanidine (referred to herein, and shown below as compound (IA)) and (+)-N-(2-chloro-5-methylthiophenyl)-Nxe2x80x2-(3-methylsulfinylphenyl)-Nxe2x80x2-methylguanidine (referred to herein, and shown below as compound (IB)). 
Compound (I) (which includes compounds I(A) and/or compound I(B)) has been found to exhibit potent neuroprotective activity. References herein to xe2x80x9ccompound (I)xe2x80x9d are intended to also refer to compound I(A) and/or compound I(B) unless otherwise specified. Those optically active compounds also can be identified as (R)-N-(2-chloro-5-methylthiophenyl)-Nxe2x80x2-(3-methylsulfinylphenyl)-Nxe2x80x2-methylguanidine (referred to herein, and shown below as compound (IA)) and (S)-N-(2-chloro-5-methylthiophenyl)-Nxe2x80x2-(3-methylsulfinylphenyl)-Nxe2x80x2-methylguanidine, pursuant to the Cahn-Ingold-Prelog convention.
Compound (I) also has been surprisingly found to exhibit significantly decreased untoward behavioral effects in a number of in vivo assays, including Irwin tests and rat rotarod motor coordination tests. See the results of Examples 8 and 9 which follow.
In a further aspect, the invention provides the compound N-(2-chloro-5-methylsulfinylphenyl)-1-(7-trifluoromethyl-1,2,3,4-tetrahydroquinolinyl) carboximidamide, and pharmaceutically acceptable salts thereof, i.e. the compound of the following structure (II): 
and pharmaceutically acceptable salts thereof References herein to xe2x80x9ccompound (II)xe2x80x9d refer to the compound of the above structure as well as pharmaceutically acceptable salts of N-(2-chloro-5-methylsulfinylphenyl)-1-(7-trifluoromethyl-1,2,3,4-tetrahydroquinolinyl)carboximidamide.
The invention includes both racemic mixtures and optically enriched mixtures of compound (II). An optically enriched mixture contains substantially more (e.g., about 60 mole %, 70 mole %, 80 mole %, 90 mole % or 95 mole % or 98 mole % or more) of one enantiomer of compound (II) than the other stereoisomer. For use in the therapeutic methods of the invention, preferably a substantially pure optically active mixture is employed, e.g. a mixture containing at least about 92 mole %, or 95 mole % or even 97 mole %, 98 mole % or 99 mole % or more of one enantiomer of compound (II).
In a yet further aspect, the invention provides the compound N-(3-methylsulfinylphenyl)-N-methyl-Nxe2x80x2-(2-chloro-5-methoxyphenyl)guanidine, and pharmaceutically acceptable salts thereof, i.e. the compound of the following structure (III): 
and pharmaceutically acceptable salts thereof. References herein to xe2x80x9ccompound (III)xe2x80x9d refer to the compound of the above structure as well as pharmaceutically acceptable salts of N-(3-methylsulfinylphenyl)-N-methyl-Nxe2x80x2-(2-chloro-5-methoxyphenyl)guanidine.
The invention includes both racemic mixtures and optically enriched mixtures of compound (III). An optically enriched mixture contains substantially more (e.g., about 60 mole %, 70 mole %, 80 mole %, 90 mole % or 95 mole % or 98 mole % or more) of one enantiomer of compound (III) than the other stereoisomer. For use in the therapeutic methods of the invention, preferably a substantially pure optically active mixture is employed, e.g. a mixture containing at least about 92 mole %, or 95 mole % or even 97 mole %, 98 mole % or 99 mole % or more of one enantiomer of compound (III).
It has been found that compounds (I), (II) and (III) are each useful for a number of therapeutic applications. In particular, the invention includes methods for treatment and/or prophylaxis of neurological conditions/injuries such as epilepsy, neurodegenerative conditions and/or nerve cell death (degeneration) resulting from e.g. hypoxia, hypoglycemia, brain or spinal chord ischemia, retinal ischemia, brain or spinal chord trauma or post-surgical neurological deficits and the like as well as neuropathic pain. The compounds of the invention are especially useful for treatment of a person susceptible or suffering from stroke or heart attack or neurological deficits relating to cardiac arrest, a person suffering or susceptible to brain or spinal cord injury, or a person suffering from the effects of retinal ischemia or degeneration. Compounds (I), (II) and (III) also are each useful to treat and/or prevent various neurodegenerative diseases such as Parkinson""s disease, Huntington""s disease, Amyotrophic Lateral Sclerosis, Alzheimer""s disease, Down""s Syndrome, Korsakoff""s disease, cerebral palsy and/or age-dependent dementia. Compounds (I), (II) and (III) will be further useful to treat and/or prevent migraines, shingles (herpes zoster), epilepsy, emesis and/or narcotic withdrawal symptoms. Also, in addition to treatment of retinal ischemia and related disorders, the invention provides methods for treatment of optic nerve injury/damage. The treatment methods of the invention in general comprise administration of a therapeutically effective amount of compound (I), (II) and/or (III) to an animal, including a mammal, particularly a human in need of treatment.
The invention also provides pharmaceutical compositions comprising a therapeutically effective amount of compound (I), (II) and/or (III) and a pharmaceutically acceptable carrier.
Other aspects of the invention are disclosed infra.